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IR reduced xenograft growth in intact mice without androgen modulation. Xenograft tumors of LAPC4 (A) and LNCaP (B) cells established in intact nude mice were exposed to sham (control) or 8Gy ionizing radiation (IR). Tumor size was longitudinally determined by caliper measurements. Graph shows relative tumor volumes normalized to the tumor size at the time of radiation.

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR).Experimental Design: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models.Results: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice.Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310–9. ©2016 AACR.See related commentary by Chua and Bristow, p. 3124

Clonogenic survival of PC3 cells following IR and DHT treatments. Clonogenic survival fraction is shown for AR negative PC3 cells exposed to vehicle control, 100 nM DHT, 4 Gy of IR or the combination of both. NS, not significant.

DNA repair genes following androgen stimulation. Androgen-deprived LNCaP cells were exposed to vehicle or 100nM DHT for the indicated times and mRNA of classical AR-regulated genes (A) or DNA repair-related genes (B) were measured using qRT-PCR. mRNA levels are expressed relative to GAPDH expression and normalized to levels in androgen-deprived conditions.

Formation of androgen induced DSB requires AR and TOP2B.

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Background: While Immune Checkpoint Inhibitors (ICI) are widely used for the treatment (tx) of patients (pts) with metastatic urothelial carcinoma (mUC), response rates are only around 20%. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment in the majority of pts who will not respond to ICI, to spare toxicity from ICI as well as mitigate the financial burden. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in a real-world cohort of mUC pts at the Cleveland Clinic. Methods: We selected 61 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-tx archival fresh frozen paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as complete responders (CR; N=8), partial responders (PR; N=14), stable disease (SD; N=9), and progressive disease (PD; N=30). Tumor was macrodissected from 2-5 FFPE slides guided by an H&E stained section of tumor. RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the 770-gene Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Using unsupervised hierarchical clustering, when comparing molecular signatures of pts with CR vs PD respectively, we saw upregulation of exhausted CD8 (log fold change (FC) = 0.7287, p= 0.03289) and IFN downstream (logFC = 0.5929, p = 0.04986). Notably, the molecular signatures upregulated between SD vs PD respectively were IFN Gamma (logFC = 1.503, p = 0.0044), PD-L1 (logFC = 1.136, p = 0.0123), Antigen-presenting machinery (APM) (logFC = 1.103, p = 0.0006), Immunoproteasome (logFC = 0.984, p = 0.00096) and Tumor inflammatory score (logFC = 0.947, p = 0.032). Furthermore, molecular signatures were not differently upregulated between pts with PR vs PD. In our cohort, the proportion of pts who were alive at 35.9 months (median follow-up) was 62.5% for CR (5 of 8), 28.5% for PR (4 of 14), 22.2% for SD (2 of 9) and 6.2% for PD (2 of 30) even though the median overall survival was not significantly different between the groups. Conclusion: In our cohort of ICI-treated mUC pts, we found an association between existing T-cell effector function, particularly IFN-gamma responses, and response to ICI. Signatures associated with T cell exhaustion were also upregulated among pts with CR indicating ongoing anti-tumor activity. These findings need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC are currently underway. Citation Format: Nikhil Pramod, Paul Pavicic, Scott Dawsey, Alan Shen, Roshan Lodha, Moshe Ornstein, Omar Mian, Timothy Gilligan, Christopher Wee, Amanda Nizam, Jane Nguyen, C. Marcela Diaz-Montero, Shilpa Gupta. Dissecting immuno-genomic pathways of response and resistance to immunotherapy in metastatic urothelial carcinoma in a real-world cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2278.

Purpose: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT). Patients and Methods: Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety. Results: In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5–33 months) with 5 patients treated >1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1–33 months) and arm B was 3 months (range: 1.5–33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events. Conclusions: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG. See related commentary by Owen and Trikalinos, p. 1748

Tribological machine components such as engine crankshaft bearings operating at high load or rotational speeds often experience very thin oil films leading to asperity contact between the bearing and crankshaft. When the oil film thickness drops below the peak asperity height there is an increase in contact, wear and asperity power loss leading to worsening severity factors and seizure risk. Key factors influencing the bearing lubrication performance are the surface characteristics of the materials at the contact interface. SABRE-TEHL is a software simulation tool used for performing thermo-elastohydrodynamic analysis of bearing applications. In this current study, the development of a combined contact and wear model is demonstrated. This includes a hard contact model giving a direct surface contact pressure in areas of zero oil film thickness, a surface yield model with yield limits and plastic gradient from measured stress–strain data, an asperity wear model using measured surface roughness data and an asperity contact model based on measured roughness, asperity density and tip radius. Input surface roughness data are measured using a white light interferometry method. The effects of surface characterization in terms of roughness and stiffness properties are demonstrated using simulation results comparing an aluminium bimetal bearing with a polymer coated bearing, showing a significant reduction in asperity friction for the bearing with a polymer coating. Simulation results are compared with experimental test results for a 1.5 l diesel engine, a 2.0 l diesel engine and for a bearing fatigue test rig. Generally good agreement is seen when comparing the wear contours and wear depth on the bearing surface.

Myeloid-derived suppressor cells (MDSC) have immunosuppressive activity and enhance tumor progression. We hypothesized that lower blood MDSC would correlate with pathologic complete response and better outcomes in nonmetastatic urothelial carcinoma (UC).Before cystectomy, blood MDSC were measured in whole blood (WB) and peripheral blood mononuclear cells using flow cytometry. MDSC were defined as CD33Overall, 109 patients were included: 86% men with median (range) age of 67 (30-88) years, 76% with pure UC, 29% intravesical therapy, and 41% neoadjuvant chemotherapy. Twenty-one patients (19%) had pT0N0 and 23 (24%) pT2N0. Median (range) follow-up time was 17.4 (0.4-42.4) months. Total MDSC and polymorphonuclear MDSC percentage in peripheral blood mononuclear cells was significantly lower in patients with pT0N0 disease (P = .03). One- and 2-year OS rates were 94% (95% confidence interval [CI], 90-99) and 83% (95% CI, 75-93), respectively. In the multivariate Cox model after adjusting for age and gender, patients with higher WB M-MDSC and UnC-MDSC had shorter OS (optimal cutoff points by recursive partitioning analysis, hazard ratio = 7.5 [95% CI, 2.5-22.8], P = .0004; hazard ratio = 3.4 [95% CI, 1.0-11.0], P = .046, respectively).In patients with nonmetastatic UC of bladder, higher WB M-MDSC and UnC-MDSC before cystectomy had negative prognostic value. Prospective validation is warranted.

Purpose: There is risk of clinical under-staging of muscle invasive bladder cancer (MIBC) by trans-urethral resection (TURBT) alone. Circulating biomarkers may improve the staging and pre-treatment risk stratification of patients with bladder cancer by discriminating non-muscle invasive (NMIBC) and MIBC. Methods: Peripheral blood from 74pts with BC (30NMIBC, 15 MIBC and 29 Met BC was collected in Streck BCT tubes and processed to obtain cfDNA. Total cfDNA quantity (ng/mlof plasma) was assessed by fluorimetry. cfDNA fragment size was measured by Bioanalyzer DNA analysis. Wilcoxon rank sum test, Cochran-armitage trend test, Fisher's exact t-test were used to compare cfDNA quantity and fragmentation pattern (small fragments are indicative of circulating tumor DNA) among pts with NMIBC, MIBC, met BC to predict invasiveness of BC. Results: There was no significant difference in cfDNA concentration between MIBC and met BC, however, cfDNA levels were significantly lower in pts with NMIBC vs MIBC and met BC. The difference was even more pronounced in case of cfDNA fragment (100-400bp) conc. Total cfDNA (ng/ml) was a good predictor in bladder cancer invasiveness, AUC 0.8 (95% CI 0.7-0.9). The risk of invasion was significantly lower inpatients with total cfDNA &lt 1.5 ng/ml and significantly higher in patients with cfDNA &gt 7.0ng/ml. In 18 pts with cfDNA&lt1.5ng/ml, only 1 pt (5.6%) had invasive cancer (at 1.2). The percent risk of invasive disease was 70.6% for cfDNA concentrations between 1.5-7.0ng/ml and 79.0% for cfDNA &gt 7.0. No invasion was observed among 13 pts with total cfDNA less than 1. This exploratory study suggests that cfDNA levels may correlate with BC stage and hence can be used in juxtaposition with TURBT, exam under anesthesia and CT to better predict clinical staging. Conclusions: Circulating cfDNA may be a dynamic, low-cost and minimally invasive biomarker that can be used in conjunction with TURBT to predict tumor invasiveness, reduce under-staging, and risk stratify patients for appropriate curative intent therapy. cfDNA variation with BC stagingcfDNA parametersTotalNMIBCMIBCMET BCp-value(N=74)(N=30)(N=15)(N=29)cfDNA_ng/ml of plasma7.3[2.9,12.5]1.3[0.48,7.4]9.7[4.0,13.3]8.7[6.1,14.4] Citation Format: Shinjini Ganguly, Jaleh Fallah, Hong Li, Wei Wei, Aysegul Balyimez, Claudia Marcela Diaz, Pat Rayman, Marcelo Lamenza, Priscilla Dann, Donna Company, Rahul Tendulkar, Jacob Scott, Mohamed Abazeed, Jorge A. Garcia, Moshe C. Ornstein, Brian R. Rini, Byron Lee, Petros Grivas, Omar Mian. Circulating cell-free DNA (cfDNA) levels and fragmentation patterns discriminate muscle invasive from non-muscle invasive urothelial cancer of the bladder [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1159.

Moderne Schmierstoffanforderungen werden immer starker von den aktuellen Umweltgesetzgebungen und dem Bauteildesign bestimmt. Die Haupttriebkrafte fur Neuentwicklungen sind kleinere Olvolumina, grosere Energieeffizienz der Verbrennung und der mechanischen Motorbauteile, geringere Umweltbelastung, Reduzierung der Wartungskosten und Ausfallspanne, langere Olwechselintervalle usw.

The implementation of CO2 saving technologies such as start–stop has introduced new constraints on the engine bearings and their operating environment. The number of expected start–stops of a modern hybrid engine has risen to about 1.2 million for the engine lifetime. Frequent operation under mixed and boundary lubrication regimes may noticeably increase wear and reduce the life of the bearings. The developed test rig and modelling software are capable of simulating engine transient working conditions. The test results confirmed higher wear resistance of a bearing with a polymeric overlay working under start–stop conditions in comparison to an aluminium bimetallic bearing. Simulation results calculated on the basis of the ‘Direct Contact Reaction’ and correlated with the experimental data made it possible to estimate the wear of the bearings working in different start–stop applications.

Under normal operating conditions, engine crankshaft bearings experience variations in oil film temperature due to shearing of the oil film. This can have a negative impact on the bearing operating life since the viscosity of the lubricant is temperature dependent. In the current study, a thermo-elastohydrodynamic lubrication (TEHL) analysis has been conducted using an in-house specialized simulation package called (software for analysis of bearings in reciprocating engines) SABRE-TEHL. This advanced simulation tool has been used to optimize a new bearing design feature leading to a significant temperature reduction, which in turn increases the robustness of the system.

A new measurement system and methodology has been developed which allows for direct measurement of the piston pin behavior of an internal combustion engine, particularly as it relates to pin joint ticking noise contributing to Noise Vibration and Harshness (NVH). Based on the measured dynamic of the piston pin during engine operation, the root cause of the pin joint ticking noise in this application was defined to be sticking of the pin at the end of the exhaust stroke which prevented pin lift. In order to better understand and mitigate this phenomenon, numerical simulation was conducted by means of Elasto Hydrodynamic Lubrication (EHL). The output of this simulation showed that modifying the shape of the connecting rod pin bore by ovality has a significant effect on the pin motion and pin acceleration which could eliminate the pin joint tick noise. This improved pin bore shape was tested in the engine and confirmed to eliminate the pin joint ticking noise by manipulating the pin motion and disallowing piston pin sticking. Finally, an analysis of the newly developed methodology to root cause and solve pin joint ticking is compared to the prior methodology.

This paper reports on the analysis of a big-end bearing in a 2.0 liter gasoline engine, using a thermo-elastohydrodynamic (TEHL) model. The analysis uses a concise and robust mass conservation algorithm together with a fast TEHL solver. Comparisons are made between the theoretical predictions and the experimental measurements of both total oil flow rate and bearing shell temperatures. Good correlation between theory and experiment was found both parameters.Copyright © 2007 by ASME

Use of lighter or compact reciprocating engine components has always been a desirable target for engine designers. Small savings in mass and dimensions here can result in significant benefits such as a reduction in total engine packaging dimensions and weight. A theoretical study of design parameters was carried out using the SABRE software programme developed by Glacier Vandervell Bearings. The results suggested that housing conformability can be favourable when applied to the cap for inertia loads but potentially detrimental when applied to the stem/big end blend. The results of a development and engine testing programme gave total rod weight savings of over 45% as compared to an existing best-in-class design.